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Although the mechanisms underpinning short-term muscle disuse atrophy and associated insulin resistance remain to be elucidated, perturbed lipid metabolism might be involved. Our aim was to determine the impact of acipimox administration [i.e., pharmacologically lowering circulating nonesterified fatty acid (NEFA) availability] on muscle amino acid metabolism and insulin sensitivity during short-term disuse. Eighteen healthy individuals (age: 22 ± 1 years; body mass index: 24.0 ± 0.6 kg·m -2 ) underwent 2 days forearm immobilization with placebo (PLA; n = 9) or acipimox (ACI; 250 mg Olbetam; n = 9) ingestion four times daily. Before and after immobilization, whole body glucose disposal rate (GDR), forearm glucose uptake (FGU; i.e., muscle insulin sensitivity), and amino acid kinetics were measured under fasting and hyperinsulinemic-hyperaminoacidemic-euglycemic clamp conditions using forearm balance and l-[ ring - 2 H 5 ]-phenylalanine infusions. Immobilization did not affect GDR but decreased insulin-stimulated FGU in both groups, more so in ACI (from 53 ± 8 to 12 ± 5 µmol·min -1 ) than PLA (from 52 ± 8 to 38 ± 13 µmol·min -1 ; P < 0.05). In ACI only, and in contrast to our hypothesis, fasting arterialized NEFA concentrations were elevated to 1.3 ± 0.1 mmol·L -1 postimmobilization ( P < 0.05), and fasting forearm NEFA balance increased approximately fourfold ( P = 0.10). Forearm phenylalanine net balance decreased following immobilization ( P < 0.10), driven by an increased rate of appearance [from 32 ± 5 (fasting) and 21 ± 4 (clamp) preimmobilization to 53 ± 8 and 31 ± 4 postimmobilization; P < 0.05] while the rate of disappearance was unaffected by disuse or acipimox. Disuse-induced insulin resistance is accompanied by early signs of negative net muscle amino acid balance, which is driven by accelerated muscle amino acid efflux. Acutely elevated NEFA availability worsened muscle insulin resistance without affecting amino acid kinetics, suggesting increased muscle NEFA uptake may contribute to inactivity-induced insulin resistance but does not cause anabolic resistance. NEW & NOTEWORTHY We demonstrate that 2 days of forearm cast immobilization in healthy young volunteers leads to the rapid development of insulin resistance, which is accompanied by accelerated muscle amino acid efflux in the absence of impaired muscle amino acid uptake. Acutely elevated fasting nonesterified fatty acid (NEFA) availability as a result of acipimox supplementation worsened muscle insulin resistance without affecting amino acid kinetics, suggesting increased muscle NEFA uptake may contribute to inactivity-induced insulin resistance but does not cause anabolic resistance.

Background: Excess accumulation of lipids leads to obesity. Triterpenoids are a group of plant compounds which poses various biological activities. The biological activities of Nimbin analogs N5 and N7 were addressed in this study on inhibiting lipid aggregation and underlying the derivatives molecular mechanisms for a therapeutical approach., Aim: This study aims to evaluate the anti-adipogenic activity of semi-natural Nimbin analogs, N5 and N7, on zebrafish larvae induced with oxidative stress due to a high-fat diet (HFD) and adipogenesis using specific fluorescent stains., Materials and Methods: Zebrafish at 4 days post fertilized (dpf) larvae were divided into groups for the HFD diet along with exposure to various concentrations of N5 and N7. HFD induced accumulation of neutral lipids and triglycerides (Oil Red O and Nile red staining, respectively) with weight gain, which generated intracellular ROS (DCFH-DA staining) and superoxide anion production (DHE staining) with depleted glutathione levels (NDA staining) were assayed. HFD exposure promoted the accumulation of inflammatory macrophages (Neutral red staining) and impaired glucose metabolism (2NBDG staining). The ability of N5 and N7 to reduce total regulating lipogenic specific genes C/EBP-α, SREBP-1 and FAS were evaluated using relative gene expression., Key Findings: The Nimbin analogues N5 and N7 suppressed adipogenesis, forming intracellular ROS and superoxide anion while simultaneously restoring glutathione levels. The analogues significantly lowered total TC and TG levels, prevented inflammatory macrophage build-up and boosted glucose absorption. Also, N5 and N7 down-regulate the lipogenic-specific genes., Significance: Nimbin analogs N5 and N7 enhance lipolysis and inhibit adipogenesis in in-vivo zebrafish larvae model., Competing Interests: Conflict of interest All the authors declare no conflict of interest regarding this work., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Flavonoids are known for potent antioxidant activity and antihyperlipidemia. As a result of the few antinutritional factors and high bioactive substances, such as flavonoids, sprouts of tartary buckwheat ( Fagopyrum tataricum , STB) have become healthy food. This study aims to unravel the antihyperlipidemic effects of STB in vivo and its potential mechanism through transcriptomic and metabonomic analysis. The physiological parameters of mice administered the high-fat diet with or without 2.5 and 5% of STB for 10 weeks were recorded. Liquid chromatography-tandem mass spectrometry and RNA sequencing were applied to obtain the serum lipid metabolomic and hepatic transcriptomic profiling, respectively. Results revealed that STB could significantly alleviate the increase of body weight, liver, and abdominal adipose while ameliorating the lipid content in serum and insulin resistance of mice fed with a high-fat diet. Notably, the metabonomic analysis identified the core differential metabolites mainly enriched in the pathways, such as fat digestion and absorption, insulin resistance, and other processes. Transcriptomic results revealed that STB significantly altered the expression levels of PIK3R1 , LRP5 , SLC10A2 , and FBXO21 . These genes are involved in the PI3K-AKT signaling pathway, digestion and absorption of carbohydrates, and type II diabetes mellitus pathways. In this study, STB exhibited remarkable influence on the metabolism of lipids and glucose, exerting antihyperlipidemic effects. STB have the potential for the development and application of a lipid-lowering health food.

One of the major complications of diabetes is diabetic nephropathy, and often many patients suffer from diabetic nephropathy. That is why it is important to find the mechanisms that cause nephropathy and its treatment. This study was designed to examine the antidiabetic effects of biochanin A (BCA) and evaluate its effects on oxidative stress markers and the expression of transforming growth factor-β1 (TGF-β1) and protease-activated receptors-2 (PAR-2) genes in the kidney of type 1 diabetic rats. After induction of diabetes using streptozotocin (STZ), 55 mg/kg bw dose, rats were randomly divided into four groups with six rats in each group as follows: normal group: normal control receiving normal saline and a single dose of citrate buffer daily; diabetic control group: diabetic control receiving 0.5% dimethyl sulfoxide daily; diabetic+BCA (10 mg/kg) group: diabetic rats receiving biochanin A at a dose of 10 mg/kg bw daily; diabetic+BCA (15 mg/kg) group: diabetic rats receiving biochanin A at a dose of 15 mg/kg bw daily. TGF-β1 and PAR-2 gene expression was assessed by real-time. Spectrophotometric methods were used to measure biochemical factors: fast blood glucose (FBG), urea, creatinine, albumin, lipids profiles malondialdehyde (MDA), and superoxide dismutase (SOD). The course of treatment in this study was 42 days. The results showed that in the diabetic control group, FBG, serum urea, creatinine, expression of TGF-β1 and PAR-2 genes, and the levels of MDA in kidney tissue significantly increased and SOD activity in kidney tissue and serum albumin significantly decreased compared to the normal group (p < 0.001). The results showed that administration of biochanin A (10 and 15 mg/kg) after 42 days significantly reduced the expression of TGF-β1 and PAR-2 genes and FBG, urea, creatinine in serum compared to the diabetic control group (p < 0.001), also significantly increased serum albumin compared to the diabetic control group (p < 0.001). The level of MDA and SOD activity in the tissues of diabetic rats that used biochanin A (10 and 15 mg/kg) was significantly reduced and increased, respectively, compared to the diabetic control group (p < 0.001). Also, the result showed that in the diabetic control group lipids profiles significantly is disturbed compared to the normal group (p < 0.001), the results also showed that biochanin A (10 and 15 mg/kg) administration could significantly improved the lipids profile compared to the control diabetic group (p < 0.001). It is noteworthy that it was found that the beneficial effects of the biochanin A were dose dependent. In conclusion, administration of biochanin A for 42 days has beneficial effect and improves diabetes and nephropathy in diabetic rats. So probably biochanin A can be used as an adjunct therapy in the treatment of diabetes., (© 2021 International Union of Biochemistry and Molecular Biology, Inc.)

This study investigates the effects of the water-soluble and organic-soluble Trichosanthes extracts on the hyperglycemic condition in streptozotocin- (STZ-) induced diabetic rats. The blood glucose levels, body weights, water intake, and urine volumes of rats in different experimental groups were monitored throughout the experiment, and the results obtained indicate that the two extracts can effectively reduce blood sugar levels, increase body weights, and improve water intake and urine volumes in diabetic rats. Based on blood biochemical analyses, the two extracts play an important role in regulating the diabetes-induced lipid metabolism disorder, increasing the levels of insulin and C-peptide, and alleviating the symptoms of diabetes. The variation in the liver glycogen contents of the water-soluble fraction and ethanol fraction groups suggests that the mechanisms underlying the hypoglycemic effects of the two extracts are different. Indeed, the water-soluble fraction alleviates diabetes symptoms in rats mainly by antioxidative activity, unlike the ethanol fraction., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Bo Zhang et al.)

In the current work, a series of novel 4-benzyloxy and 4-(2-phenylethoxy) chalcone fibrate hybrids (10a-o) and (11a-e) were synthesized and evaluated as new PPARα agonists in order to find new agents with higher activity and fewer side effects. The 2-propanoic acid derivative 10a and the 2-butanoic acid congener 10i showed the best overall PPARα agonistic activity showing E max % values of 50.80 and 90.55%, respectively, and EC 50 values of 8.9 and 25.0 μM, respectively, compared to fenofibric acid with E max  = 100% and EC 50  = 23.22 μM, respectively. These two compounds also stimulated carnitine palmitoyltransferase 1A gene transcription in HepG2 cells and PPARα protein expression. Molecular docking simulations were performed for the newly synthesized compounds to study their predicted binding pattern and energies in PPARα active site to rationalize their promising activity. In vivo, compounds 10a and 10i elicited a significant hypolipidemic activity improving the lipid profile in triton WR-1339-induced hyperlipidemic rats, including serum triglycerides, total cholesterol, LDL, HDL and VLDL levels. Compound 10i possessed better anti-hyperlipidemic activity than 10a. At a dose of 200 mg/kg, it demonstrated significantly lower TC, TG, LDL and VLDL levels than that of fenofibrate at the same dose with similar HDL levels. Compounds 10i and 10a possessed atherogenic indices (CRR, AC, AI, CRI-II) like that of fenofibrate. Additionally, a promising antioxidant activity indicated by the increased tissue reduced glutathione and plasma total antioxidant capacity with decreased plasma malondialdehyde levels was demonstrated by compounds 10a and 10i. No histopathological alterations were recorded in the hepatic tissue of compound 10i (200 mg/kg)., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Hyperlipidemia is recognized as one of the most important risk factors for morbidity and mortality due to cardiovascular diseases. Daming capsule, a Chinese patent medicine, has shown definitive efficacy in patients with hyperlipidemia. In this study, serum biochemistry and histopathology assessment were used to investigate the lipid-lowering effect of Daming capsule. Furthermore, urinary metabolomics based on ultra high performance liquid chromatography with quadrupole time-of-flight mass spectrometry was conducted to identify the urinary biomarkers associated with hyperlipidemia and discover the underlying mechanisms of the antihyperlipidemic action of Daming capsule. After 10 weeks of treatment, Daming capsule significantly lowered serum lipid levels and ameliorated hepatic steatosis induced by a high-fat diet. A total of 33 potential biomarkers associated with hyperlipidemia were identified, among which 26 were robustly restored to normal levels after administration of Daming capsule. Pathway analysis revealed that the lipid-lowering effect of Daming capsule is related to the regulation of multiple metabolic pathways including vitamin B and amino acid metabolism, tricarboxylic acid cycle, and pentose phosphate pathway. Notably, the study demonstrates that metabolomics is a powerful tool to elucidate the multitarget mechanism of traditional Chinese medicines, thereby promoting their research and development., (© 2021 Wiley-VCH GmbH.)

Background: Hyperlipidemia is one of the metabolic disorders that poses a great threat to human health. This study is aimed at investigating the potential hypolipidemic properties of extract from peanut meal fermented with Bacillus natto and Monascus in mice fed with a high-fat diet. Herein, 60 male C57BL/6J mice were randomly divided into six groups: four control groups, comprised of a normal group, a model (M) group, a positive control group (atorvastatin 10 mg kg -1 ), and a nonfermented peanut meal extract group (150 mg kg -1 ), and two experimental groups, comprised of a fermented peanut meal extract low-dose group (50 mg kg -1 ) and a fermented peanut meal extract high-dose group (FH, 150 mg kg -1 )., Results: Body weight (P = 0.001) and levels of serum total cholesterol (P = 0.007), triacylglycerol (P = 0.040), low-density lipoprotein cholesterol (P < 0.001), and leptin (P < 0.001) were remarkably decreased in the FH group, whereas the serum high-density lipoprotein cholesterol levels were increased (P < 0.001) by 78.3% compared with the M group. Ileum tissue stained with hematoxylin and eosin showed that the ileal villus detachments in mice were improved, and the villus height was increased by supplementation with extract from fermented peanut meal. Moreover, the expressions of intestinal ZO-1 (P = 0.003) and occludin (P = 0.013) were elevated in the FH group, compared with the M group., Conclusion: Extract of peanut meal fermented by B. natto and Monascus can effectively improve hyperlipidemia caused by a high-fat diet in mice, via regulating leptin and blood lipid levels, and protect the intestinal mucosal barrier, which provides evidence for its anti-hyperlipidemia effects and is a research basis for potential industrial development. © 2020 Society of Chemical Industry., (© 2020 Society of Chemical Industry.)

Omega-3 fatty acids from fish oil reduce triglyceride levels in mammals, yet the mechanisms underlying this effect have not been fully clarified, despite the clinical use of omega-3 ethyl esters to treat severe hypertriglyceridemia and reduce cardiovascular disease risk in humans. Here, we identified in bile a class of hypotriglyceridemic omega-3 fatty acid-derived N-acyl taurines (NATs) that, after dietary omega-3 fatty acid supplementation, increased to concentrations similar to those of steroidal bile acids. The biliary docosahexaenoic acid-containing (DHA-containing) NAT C22:6 NAT was increased in human and mouse plasma after dietary omega-3 fatty acid supplementation and potently inhibited intestinal triacylglycerol hydrolysis and lipid absorption. Supporting this observation, genetic elevation of endogenous NAT levels in mice impaired lipid absorption, whereas selective augmentation of C22:6 NAT levels protected against hypertriglyceridemia and fatty liver. When administered pharmacologically, C22:6 NAT accumulated in bile and reduced high-fat diet-induced, but not sucrose-induced, hepatic lipid accumulation in mice, suggesting that C22:6 NAT is a negative feedback mediator that limits excess intestinal lipid absorption. Thus, biliary omega-3 NATs may contribute to the hypotriglyceridemic mechanism of action of fish oil and could influence the design of more potent omega-3 fatty acid-based therapeutics.

Maha yogaraja guggulu (MYG) is a classical herbomineral polyherbal formulation being widely used since centuries. The aim of this study was to investigate the effect of MYG formulation and its major constituents E & Z guggulsterone on CYP3A4 mediated metabolism. In vitro inhibition of MYG and Guggulsterone isomers on CYP3A4 was evaluated by high throughput fluorometric assay. Eighteen Adult male Sprague-Dawley rats (200 ± 25 g body weight) were randomly divided into three groups. Group A, Group B and Group C were treated with placebo, MYG and Standard E & Z guggulsterone for 14 days respectively by oral route. On 15th day, midazolam (5 mg/kg) was administered orally to all rats in each group. Blood samples (0.3 mL) were collected from the retro orbital vein at 0.25, 0.5, 0.75, 1, 2, 4, 6, 12 and 24 h of each rat were collected. The findings from the in vitro & in vivo study proposed that the MYG tablets and its guggulsterone isomers have drug interaction potential when consumed along with conventional drugs which are CYP3A4 substrates. In vivo pharmacokinetic drug interaction study of midazolam pointed out that the MYG tablets and guggulsterone isomers showed an inhibitory activity towards CYP3A4 which may have leads to clinically significant interactions.

Icariin has a variety of biological activities, such as lipid-lowering effects, and has attracted widespread attention in recent years. However, it is not clear whether lipid-lowering effect is that multiple metabolites or a particular component plays a major role. It is known that icariin has a variety of metabolites in the body, including icariside I, icariside II, icaritin, desmethylicaritin, and other metabolites. Many of these studies have shown that the metabolites of icariin have a lipid-lowering effect. This paper focuses on the lipid-regulating effects of icariin and its metabolites in vitro and in vivo, and highlights the mechanisms involved. Icariin may have potential in the development of therapeutic strategies to regulate lipid metabolism., (Copyright © 2020 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)

Oxidative stress, inflammation and gut microbiota disorders can be induced by long-term high-fat diets (HFD). In order to confirm that polyphenols can improve these symptoms, polyphenols from Shanxi-aged vinegar (SAVEP) were extracted, and the components were detected by Comprehensive two-dimensional gas chromatography mass spectrometry (GC × GC-MS). 41 polyphenols include 18 phenolic acids and 17 polyphenols, which have not been reported. The mechanism of SAVEP on oxidative stress and inflammatory stress induced by HFD in rats and its regulating effect on intestinal flora disorder were studied. The results showed that SAVEP could significantly improve the lipid, inflammatory stress and oxidative stress related indicators compared with the Model group ("Model" refers to the group that successfully constructed a hyperlipidemia model by feeding HFD without any drugs or SAVEP in subsequent experiments.). In addition, SAVEP decreased the Firmicutes/Bacteroidetes ratio compared with the Model group, and elevated the relative abundance of beneficial bacteria. Conclusively, SAVEP can alleviate the oxidative stress and inflammatory stress caused by HFD, improving intestinal microbial disorders. The Spearman's correlation analysis revealed that Desulfovibrio, Lactobacillus and Akkermansia were correlated negatively with all of the inflammatory indicators, whereas Ruminococcus was the opposite. These results suggest that SAVEP may be a novel strategy against oxidative stress and inflammation, restoring the normal microbial community ecology of the gut and the treatment of metabolic syndromes.

Background & Aims: Circulating peptides and G protein-coupled receptors (GPCRs) have gained much attention because of their biofunctions in metabolic disorders including obesity and non-alcoholic fatty liver disease (NAFLD). Herein, we aimed to characterize the role and therapeutic potential of a newly identified peptide hormone in NAFLD., Methods: Using bioinformatics, we identified a murine circulating pentadecapeptide flanked by potential convertase cleavage sites of osteocalcin (OCN), which we named 'metabolitin (MTL)'. We used ligand-receptor binding, receptor internalization, bioluminescence resonance energy transfer and Nano isothermal titration calorimetry assays to study the binding relationship between MTL and GPRC6A. For in vivo biological studies, wild-type mice kept on a high-fat diet (HFD) were injected or gavaged with MTL to study its function in NAFLD., Results: We confirmed that MTL binds to GPRC6A and OCN interacts with GPRC6A using in vitro biological studies. Both intraperitoneal and oral administration of MTL greatly improved NAFLD and insulin resistance in a mouse model. Interacting with GPRC6A expressed in intestines, MTL can significantly inhibit intestinal neurotensin secretion, which in turn inhibits triglyceride but not cholesterol gut absorption, mediated by the 5'AMP-activated protein kinase pathway. In addition, glucagon like peptide-1 secretion was induced by MTL treatment., Conclusions: Oral or intraperitoneal MTL significantly improves the symptoms of NAFLD by inhibiting lipid absorption and insulin resistance. MTL could be a potential therapeutic candidate for the treatment of NAFLD., Lay Summary: A novel murine peptide hormone, herein named 'metabolitin', inhibits fatty acid absorption and improves systemic insulin resistance in a murine model of obesity and non-alcoholic fatty liver disease. Thus, metabolitin has therapeutic potential for the treatment of patients with non-alcoholic fatty liver disease., Competing Interests: Conflict of interest The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

In vitro permeability and in vivo pharmacokinetics of pemafibrate were investigated in human intestinal and animal models untreated or pretreated with cyclosporine A or rifampicin to evaluate any drug interactions. Ratios of basal to apical apparent permeability (P app ) over apical to basal P app in the presence of pH gradients decreased from 0.37 to 0.080 on rifampicin co-incubation, suggesting active transport of pemafibrate from basal to apical sides in intestinal models. Plasma concentrations of intravenously administered pemafibrate were enhanced moderately in control mice but only marginally in humanized-liver mice by oral pretreatment with rifampicin [an organic anion transporting polypeptide (OATP) 1B1 inhibitor] 1 h before the administration of pemafibrate. In three cynomolgus monkeys genotyped as wild-type OATP1B1 (2 homozygous and 1 heterozygous), oral dosing of cyclosporine A 4 h or rifampicin 1 h before pemafibrate administration significantly increased the areas under the plasma concentration-time curves (AUC) of intravenously administered pemafibrate by 4.9- and 7.4-fold, respectively. Plasma AUC values of three pemafibrate metabolites in cynomolgus monkeys were also increased by cyclosporine A or rifampicin. These results suggested that pemafibrate was actively uptaken in livers and rapidly cleared from plasma in cynomolgus monkeys; this rapid clearance was suppressible by OATP1B1 inhibitors., Competing Interests: Declaration of competing interest S.O. is a visiting scientist in academia and works for Kowa Co., the manufacturer of pemafibrate. The other authors declare that there are no conflicts of interest., (Copyright © 2020 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.)

Bioassay-guided fractionation of an ethanolic extract of Ochrosia borbonica led to the isolation of two known pyridocarbazole alkaloids, ellipticine (1) and 9-methoxyellipticine (2), and six known monoterpenoid indole alkaloids (3-8). Lipid-lowering assay in 3T3-L1 cell model revealed that 1 and 2 could significantly inhibit the lipid droplet formation (EC 50 = 0.41 and 0.92 μmol·L -1 , respectively) and lower triglyceride levels by 50%-60% at the concentration of 1 μmol·L -1 , being more potent than the positive drug luteolin (EC 50 = 2.63 μmol·L -1 ). A mechanistic study indicated that 1 and 2 could intercalate into supercoiled DNA, which consequently inhibited the mitotic clonal expansion of 3T3-L1 cells at the early differentiation phase, leading to the retardance of following adipogenesis and lipogenesis. These findings suggest that 1 and 2 may serve as promising leads for further development of anti-obesity drugs., (Copyright © 2019 China Pharmaceutical University. Published by Elsevier B.V. All rights reserved.)

Coffee parchment was evaluated as a potential dietary fiber ingredient. For this purpose, dietary fiber was extracted by enzymatic and non-enzymatic methods and its physicochemical and in vitro hypoglycemic and hypolipidemic properties were investigated. Results revealed that coffee parchment (flakes and flour) was a good source of insoluble dietary fiber (IDF), mainly composed by xylans (35%), lignin (32%), and cellulose (12%). From results, the IDF extraction seemed not to be required the use of enzymes. Coffee parchment did not stand out by its content of phenolic compounds and antioxidant capacity, but milling process improved them. Due to its physical structure, coffee parchment flakes exhibited high oil holding capacity (3.8 mg L -1 ), gelation capacity (8%) besides hydration properties, including water holding (3.4 mg L -1 ), absorption (3.0 mg L -1 ) and swelling (14 mg L -1 ) capacities. Its flour and water-insoluble residue showed lower capacities. Nevertheless, these coffee parchment samples presented effective in vitro hypoglycemic properties, showing high glucose adsorption capacity (50-200 mmol L -1 ), and capacity to decrease its diffusion (13%), and to inhibit α-amylase (52%) that led to lower starch digestibility (until 46%); and also, outstanding in vitro hypolipidemic properties, as inhibition of pancreatic lipase (43%) and binding of cholesterol and sodium cholate (16.6 and 35.3 mg g -1 , respectively). These results provide valuable information for the potential use of coffee parchment as new food DF ingredient., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

In our continued effort to discover novel PTP1B inhibitor with improved in vivo activity, we attempted to optimize our previously discovered lead compound by replacing the sulfonyl group with benzoyl group to yield compound II. Additional structural modifications were performed on compound II to yield a series of 24 aryl phenylthiazolyl phenylcarboxamides as potential PTP1B inhibitors. Of the 24 tested, 6 compounds showed good PTP1B inhibitory activity while compound 38 as the most promising one. The plausible PTP1B-binding site interaction of compound 38 showed favourable binding similar to known PTP1B binders and suggests its selectivity towards PTP1B. Compound 38 also showed promising antihyperglycaemic, antidyslipidaemic and insulin resistant reversal activities in vivo in STZ model and db/db mice model. Altogether, the compound 38 presents an excellent candidate for future PTP1B targeted drug discovery., (© 2019 John Wiley & Sons A/S.)

Ezetimibe (EZE) is an extensively used antihyperlipidemic drug with an important cholesterol lowering activity. It undergoes extensive first-pass metabolism to form its active glucuronide metabolite (EZEG). Both drugs exhibit complex pharmacokinetic profiles attributed mainly to repetitive enterohepatic kinetics. The aim of the present study was the investigation of EZE and EZEG pharmacokinetics (PK), through the development of a joint population pharmacokinetic model able to characterize their kinetic processes and enterohepatic recirculation simultaneously. Concentration-time data derived from a bioequivalence study in 28 healthy subjects were used for the analysis. Population PK modeling was performed on the obtained data using nonlinear mixed effect modeling approach, where different methodologies were applied for the description of the complex metabolism and recirculation processes of the two compounds. EZE and EZEG concentrations were best described by a population PK model incorporating first-pass metabolism and an enterohepatic recirculation loop, accounting for the recycling process of the two moieties. This is the first joint population pharmacokinetic model describing the kinetics of both EZE and EZEG., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Coconut oil has gained in popularity over recent years as a healthy oil due to its potential cardiovascular benefits. Coconut oil contains medium chain triglycerides (MCT) including lauric acid and capric acid that display beneficial properties in human health. Licorice ( Glycyrrhiza uralensis) is used as a sweetener and in traditional Chinese medicine with anti-inflammatory, antimicrobial, and antioxidant activities. This study investigated the in vivo effects of medium chain-triglycerides (MCT)-coconut oil (MCO) and its combination with licorice extract (LE-MCO) on serum lipid profile, hepatic steatosis, and local fat pad proteins in diet-induced obese mice. No liver toxicity was observed in 45% fat diet (HFD)-fed mice orally treated with LE, MCO, and LE-MCO for 12 weeks. Their supplementation reduced HFD-enhanced body weight, blood glucose, and insulin in mice. Plasma levels of both PLTP and LCAT were boosted in LE-MCO-administered mice. Supplementation of LE-MCO diminished plasma levels of TG and TC with concomitant reduction of the LDL-C level and tended to raise blood HDL-C level compared to that of HFD alone-mice. Treatment of LE-MCO encumbered the hepatic induction of hepatosteatosis-related proteins of SREBP2, SREBP1c, FAS, ACC, and CD36 in HFD-fed mice. Substantial suppression of this induction was also observed in the liver of mice treated with MCO. Oral administration of LE-MCO to HFD mice boosted hepatic activation of AMPK and the induction of UCP-1 and FATP1 in brown fat. Conversely, LE-MCO disturbed hepatic PPAR-LXR-RXR signaling in HFD-fed animals and reversed HFD-elevated epididymal PPARγ. Collectively, oral administration of LE-MCO may impede hyperlipidemia and hepatosteatosis through curtailing hepatic lipid synthesis.

In the modern era, cardiovascular biomarkers are often measured in the presence of medication use, such that the observed biomarker value for the treated participants is different than their underlying natural history value. However, for certain predictors (e.g. age, gender, and genetic exposures) the observed biomarker value is not of primary interest. Rather, we are interested in estimating the association between these predictors and the natural history of the biomarker that would have occurred in the absence of treatment. Nonrandom medication use obscures our ability to estimate this association in cross-sectional observational data. Structural equation methodology (e.g. the treatment effects model), while historically used to estimate treatment effects, has been previously shown to be a reasonable way to correct endogeneity bias when estimating natural biomarker associations. However, the assumption that the effects of medication use on the biomarker are uniform across participants on medication is generally not thought to be reasonable. We derive an extension of the treatment effects model to accommodate effect modification. Based on several simulation studies and an application to data from the Multi-Ethnic Study of Atherosclerosis, we show that our extension substantially improves bias in estimating associations of interest, particularly when effect modifiers are associated with the biomarker or with medication use, without a meaningful cost of efficiency.

We have previously reported the lipid-lowering effects of a Korean rice cookie called dasik (RCD) in comparison with a western style cookie. In this study, Schisandra chinensis (Turcz.) Baill. (Chinese magnolia vine) fruit-supplemented RCD (SRCD) was added to a diet, and the hypolipidemic and antidiabetic effects of different diets were examined by using the ICR and db/db mouse models, respectively. ICR mice were fed the AIN-76 diet, or high-fat diet (HFD), or the RCD- or SRCD-supplemented HFD (10%, w/w) for 9 weeks (n = 7 per group). Compared with the RCD group, plasma and hepatic triglyceride and cholesterol concentrations were decreased in the SRCD group. Hepatic expressions for fatty acid and cholesterol synthesis were downregulated, whereas those for beta-oxidation and cholesterol export were upregulated (P < .05). The antidiabetic effects of SRCD were tested in db/db mice for 10 weeks (n = 7 per group). Glucose tolerance was improved in the SRCD group through the regulation of gluconeogenic enzymes and biomarkers related to the insulin signaling pathway (P < .05). In addition, SRCD increased the expression levels of antioxidative enzymes, and decreased those of inflammatory cytokines (P < .05). Moreover, oxidative stress, leptin, and insulin levels were lower in the SRCD group than in the other groups (P < .05). In conclusion, the lipid-lowering and antidiabetic effects of SRCD were greater than those of RCD with respect to the suppression of lipid synthesis, oxidative stress, and inflammation and the improvement of glucose metabolism.

The elevated blood levels of cholesterol and low-density lipoproteins result in hyperlipidemia. The available expensive prophylactic treatments are kindred with severe side effects. Therefore, we fabricated the polymeric nanoparticles of gamma-oryzanol to achieving the improved efficacy of drug. The nanoparticles were prepared by ionic gelation method and optimized using 2 3 full factorial design taking drug/polymer ratio (X 1 ), polymer/cross linking agent ratio (X 2 ), and stirring speed (X 3 ) as independent variables. The average particle size, percentage entrapment efficiency, and in vitro drug release at 2, 12, and 24 h were selected as response parameters. The factorial batches were statistically analyzed and optimized. The optimized nanoparticles were characterized with respect to particle size (141 nm) and zeta potential (+ 6.45 mV). Results obtained with the prepared and characterized formulation showed 83% mucoadhesion towards the intestinal mucosa. The in vitro findings were complemented well by in vivo anti-hyperlipidemic activity of developed formulation carried out in Swiss albino mouse model. The in vivo studies showed improved atherogenic index, malondialdehyde, and superoxide dismutase levels in poloxamer-407-induced hyperlipidemic animals when treated with oryzanol and gamma-oryzanol nanoformulation. Based on our findings, we believe that chitosan-mediated delivery of gamma-oryzanol nanoparticles might prove better in terms of anti-hyperlipidemic therapeutics.

Previous studies have shown that fermentations can enhance the bioactivity and absorption rate of soybean products. Fermented soybean products can alleviate hyperlipidemia and decrease risks of atherosclerosis and cardiovascular diseases. This study aimed to investigate the effects and mechanisms of soymilk fermented by Lactococcus acidophilus on blood lipids and antioxidant enzyme activities of rats fed with a high fat diet. Sixty rats were randomly assigned to six groups: normal control group (NC), high-fat control group (HFC), positive control group (cholestyramine, PC), Lactococcus acidophilus group (LA), soymilk group (SM), and fermented soymilk group (FSM), respectively. The NC group was fed with a basic diet, while the other groups were fed with a high-fat diet. After the experimental period (6 W), rats were sacrificed by decapitation. Blood and liver were collected to measure the concentrations of lipids and antioxidant enzyme activities. Results demonstrated that fermented soymilk could regulate lipid levels, restore HDL-c and TG to normal levels, and lower the concentrations of LDL-c than hypolipidemic drugs in hyperlipidemia rats. More importantly, fermented soymilk caused significant reduction in arteriosclerosis index and coronary risk index. Fermented soymilk also improved antioxidant capacities of hyperlipidemia rats. The increase of aglycone isoflavones in fermented soymilk could explain the above phenomena. In conclusion, soymilk fermented by Lactococcus acidophilus reduced risks of arteriosclerosis and coronary heart disease by regulating lipid levels and improving the antioxidant capacities of hyperlipidemia rats.

In the bamboo shoot processing industries, bamboo shoot shells are discarded without any utilization. As a cheap potential dietary fibers resource, bamboo shoot (Leleba oldhami Nakal) shell was decomposed to dietary fibers by multiple enzymes. The extraction yields of insoluble dietary fiber and soluble dietary fiber were 56.21% and 8.67%, respectively. The resulting fibers showed significant swelling capacity, water holding capacity and exhibit in vitro binding capacities to fat, cholesterol, bile acids and nitrites. The administration of bamboo shoot shell fibers improved the lipid metabolism disorderly situation of hyperlipidemia mice. Compared with normal group, total dietary fiber supplement could exhibit the lowest body weight gain (2.84%) in mice, and decrease total cholesterol, triglyceride and low density lipoprotein-cholesterol by 31.53%, 21.35% and 31.53%, respectively; while it can increase high density lipoprotein-cholesterol by 37.6%. The bamboo shoot shell fibers could be a potentially available dietary ingredient in functional food industries., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Hypothesis: Synthetic sugar alcohol mono-behenates with high melting points, surface activity and resistance to enzymatic lipolysis, are expected to form stable single-component solid lipid nanocarriers (SC-SLNs). The preparation methods and the polar head group of the molecules should affect the size and drug encapsulation efficiency., Experiments: SC-SLNs of sugar alcohol mono-behenates with varied polar heads were prepared using emulsification-diffusion method and melting-probe sonication method. Model lipophilic drug fenofibrate was formulated into nanocarriers. The drug release was assessed using the lipolysis model. The structure and drug distribution of the nanocarriers were studied using AFM and TEM., Findings: Both the polar head group of the molecules and the preparation methods affect the particle size and size distribution. Nanocarriers prepared with sorbitol mono-behenates showed the smallest mean size (∼100nm with PdI of 0.26). In addition, they displayed high entrapment efficiency of fenofibrate (95%) and long term drug release. Nanocarriers prepared by emulsification-diffusion method entrapped fenofibrate into lipid bilayers. In contrast, Nanocarriers prepared by melting-probe sonication method had a micelle structure with fenofibrate incorporated into a lipid monolayer. This study provides an insight into the systematic development of novel amphiphilic lipids for solid lipid-based drug delivery system., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objectives: Mesoporous silicas (SLC) have demonstrated considerable potential to improve bioavailability of poorly soluble drugs by facilitating rapid dissolution and generating supersaturation. The addition of certain polymers can further enhance the dissolution of these formulations by preventing drug precipitation. This study uses fenofibrate as a model drug to investigate the performance of an SLC-based formulation, delivered with hydroxypropyl methylcellulose acetate succinate (HPMCAS) as a precipitation inhibitor, in pigs. The ability of biorelevant dissolution testing to predict the in vivo performance was also assessed., Key Findings: Fenofibrate-loaded mesoporous silica (FF-SLC), together with HPMCAS, displayed significant improvements in biorelevant dissolution tests relative to a reference formulation consisting of a physical mixture of crystalline fenofibrate with HPMCAS. In vivo assessment in fasted pigs demonstrated bioavailabilities of 86.69 ± 35.37% with combination of FF-SLC and HPMCAS in capsule form and 75.47 ± 14.58% as a suspension, compared to 19.92 ± 9.89% with the reference formulation. A positive correlation was identified between bioavailability and dissolution efficiency., Conclusions: The substantial improvements in bioavailability of fenofibrate from the SLC-based formulations confirm the ability of this formulation strategy to overcome the dissolution and solubility limitations, further raising the prospects of a future commercially available SLC-based formulation., (© 2017 Royal Pharmaceutical Society.)

We hypothesized that hepatic steatosis could be mitigated by the hypolipidemic activity of Schisandra chinensis berry ethanol extract (SCE) via the inhibition of histone acetyltransferase (HAT) activity. HepG2 cells treated with oleic acid (OA) in the presence of SCE exhibited reduced OA-induced lipid accumulation, which was likely mediated by reductions in SREBP-1c expression. SCE attenuated the acetylation of total lysine and H3K9 that was otherwise increased by OA. Male obese mice fed with either a low-fat diet or Western diet exhibited reduced body and liver weights when supplemented with 1% SCE. The SCE-mediated attenuation of hepatic lipid accumulation was accompanied by a decrease in the expression of lipogenic genes. SCE also attenuated the expression of acetylated lysine and non-acetylated forms of H3K9 acetylation in the livers of these mice. Taken together, these results suggest that SCE has potential for further development as a novel therapeutic agent for the prevention of steatosis., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Bergamot polyphenolic fraction (BPF) has been shown to positively modulate several mechanisms involved in metabolic syndrome, suggesting its use in therapy. In particular, it is able to induce a significant amelioration of serum lipid profile in hyperlipemic patients at different levels. The purpose of our study was to investigate the effect of BPF on cholesterol absorption physiologically mediated by pancreatic cholesterol ester hydrolase (pCEH). An in vitro activity assay was performed to study the effect of BPF on pCEH, whereas the rate of cholesterol absorption was evaluated through in vivo studies. In particular, male, Sprague-Dawley rats (200–225 g) were fed either normal chow or chow supplemented with 0.5% cholic acid, 5.5% peanut oil, and varying amounts of cholesterol (0 to 1.5%). BPF (10 mg/Kg) was daily administrated by means of a gastric gavage to animals fed with lipid supplemented diet for 4 weeks and, at the end of the study, plasma lipids and liver cholesteryl esters were measured in all experimental groups. Our results show that BPF was able to inhibit pCEH activity and this effect was confirmed, in vivo, via detection of lymphatic cholesteryl ester in rats fed with a cholesterol-rich diet. This evidence clarifies a further mechanism responsible for the hypolipemic properties of BPF previously observed in humans, confirming its beneficial effect in the therapy of hypercholesterolemia and in the treatment of metabolic syndrome.

Background: Details regarding the functional properties of paprika seed oil are relatively scarce. In this study the hypolipidaemic effects and mechanisms of paprika seed oil on Sprague-Dawley rats are explored, which may improve the usage of paprika seed source and provide a theoretical basis of paprika seed oil for the alleviation of hyperlipidaemia., Results: In capsaicin and paprika seed oil (PSO) groups, total cholesterol (TC) and total triglyceride (TG) in serum and liver lipids of rats were significantly decreased (P < 0.05). The contents of serum HDL cholesterol were increased and the contents of serum LDL cholesterol were decreased (P < 0.05). Real-time PCR analyses revealed that the hepatic mRNA expression of fatty acid synthetase (FAS) is decreased and the expression levels of HSL is increased (P < 0.05). The mRNA expression of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) is decreased and the expression levels of low-density lipoprotein receptor (LDLR) is significantly improved (P < 0.05). The cholesterol 7-hydroxylase (CYP7A1) expression is regulated to control the cholesterol-to-bile acid transformation and cholesterol excretion is promoted. Capsaicin and unsaturated fatty acid PSO can activate and improve the mRNA expression of transient receptor potential vanilloid type-1 (TRPV1) and peroxisome proliferators-activated receptors (PPARα)., Conclusion: The hypolipidaemic effects of paprika seed oil (PSO) may be attributed to the inhibition of lipid synthesis via suppressing the expression of HMG-CoAR, CYP7A1 and FAS, meanwhile, promoting the metabolism and excretion of lipids via up-regulating the expression of LDLR, HSL, TRPV1 and PPARα. © 2017 Society of Chemical Industry., (© 2017 Society of Chemical Industry.)

The current studies sought to explore the impact of drug supersaturation and precipitation during the dispersion and digestion of lipid-based formulations (LBFs), on in vivo absorption using a coupled in vitro digestion-in vivo perfusion absorption model. Fenofibrate absorption was evaluated from a number of LBFs with different solubilization and supersaturation capacities, and conditions at the absorptive membrane manipulated by changing perfusion conditions, intestine segment lengths, and by the conduct of experiments in the presence or absence of suspended/precipitated drug. LBF dispersion and digestion resulted in varying periods of supersaturation across the different formulations. Even fleeting (5-10 min) periods of supersaturation were able to drive flux across a perfused 10 cm intestinal segment for up to 60 min, although over longer infusion periods (60-80 min) flux dropped in the absence of ongoing drug solubilization and supersaturation. In contrast, the presence or absence of precipitated/suspended drug, had little impact on drug flux. When perfused intestinal segment lengths were extended, the role of initial supersaturation was attenuated and ongoing solubilization conditions became the primary driver of absorptive flux. The data suggest that for highly permeable drugs such as fenofibrate, a short period of supersaturation at the absorptive membrane may be sufficient to drive absorptive drug flux in spite of significant drug precipitation on formulation dispersion or digestion in vitro. In contrast, where longer periods of absorption are required, for example, at higher doses, the requirement for ongoing solubilization and supersaturation becomes more apparent.

Dyslipidemia is recognized as a major cause of cardiovascular disease. A number of evidence-based guidelines recommend conventional synthetic drugs as standard therapy for dyslipidemia in clinical practice. However, antihyperlipidemic drugs have some serious side effects. Naturally derived dietary supplements are becoming attractive as an alternative strategy because of their high efficacy and safety, as supported by numerous data. Moreover, they could be considered an initial treatment for dyslipidemia. The aims of this literature review were to demonstrate the efficacy, safety, and clinical implications of dietary supplements for treating dyslipidemia. We reviewed the literature, including data from in vitro, in vivo, and human studies, and clinical guideline recommendations. We classified dietary supplements by their proposed mechanisms of action on lipid metabolism and also collected daily dosage recommendations, interactions with concurrent drugs and/or foods, dosage forms, and examples of commercially available products. Various types of naturally derived dietary supplements exhibit lipid-improving properties. Efficacy and safety are acceptable; however, their use in clinical practice will require further well-designed investigations and the support of scientific data.

Objective: Recently, we have shown that Bezafibrate (BEZ), the pan-PPAR (peroxisome proliferator-activated receptor) activator, ameliorated diabetes in insulin deficient streptozotocin treated diabetic mice. In order to study whether BEZ can also improve glucose metabolism in a mouse model for fatty liver and type 2 diabetes, the drug was applied to TallyHo mice., Methods: TallyHo mice were divided into an early (ED) and late (LD) diabetes progression group and both groups were treated with 0.5% BEZ (BEZ group) or standard diet (SD group) for 8 weeks. We analyzed plasma parameters, pancreatic beta-cell morphology, and mass as well as glucose metabolism of the BEZ-treated and control mice. Furthermore, liver fat content and composition as well as hepatic gluconeogenesis and mitochondrial mass were determined., Results: Plasma lipid and glucose levels were markedly reduced upon BEZ treatment, which was accompanied by elevated insulin sensitivity index as well as glucose tolerance, respectively. BEZ increased islet area in the pancreas. Furthermore, BEZ treatment improved energy expenditure and metabolic flexibility. In the liver, BEZ ameliorated steatosis, modified lipid composition and increased mitochondrial mass, which was accompanied by reduced hepatic gluconeogenesis., Conclusions: Our data showed that BEZ ameliorates diabetes probably via reduced steatosis, enhanced hepatic mitochondrial mass, improved metabolic flexibility and elevated hepatic insulin sensitivity in TallyHo mice, suggesting that BEZ treatment could be beneficial for patients with NAFLD and impaired glucose metabolism.

Introduction: Cytochrome P450 (CYP) 2C8 is a drug metabolizing enzyme of major importance. The lipid-lowering drug gemfibrozil has been identified as a strong inhibitor of CYP2C8 in vivo. This effect is due to mechanism-based inhibition of CYP2C8 by gemfibrozil 1-O-β-glucuronide. In vivo, gemfibrozil is a fairly selective CYP2C8 inhibitor, which lacks significant inhibitory effect on other CYP enzymes. Gemfibrozil can, however, have a smaller but clinically meaningful inhibitory effect on membrane transporters, such as organic anion transporting polypeptide 1B1 and organic anion transporter 3. Areas covered: This review describes the inhibitory effects of gemfibrozil on CYP enzymes and membrane transporters. The clinical drug interactions caused by gemfibrozil and the different mechanisms contributing to the interactions are reviewed in detail. Expert opinion: Gemfibrozil is a useful probe inhibitor of CYP2C8 in vivo, but its effect on membrane transporters has to be taken into account in study design and interpretation. Moreover, gemfibrozil could be used to boost the pharmacokinetics of CYP2C8 substrate drugs. Identification of gemfibrozil 1-O-β-glucuronide as a potent mechanism-based inhibitor of CYP2C8 has led to recognition of glucuronide metabolites as perpetrators of drug-drug interactions. Recently, also acyl glucuronide metabolites of clopidogrel and deleobuvir have been shown to strongly inhibit CYP2C8.

In this article, we consider the new drugs approved for the European market in 2015. We present a summary of the new mechanisms of action introduced and highlight three new mechanisms of action with a potentially high future impact: PCSK9 inhibition (alirocumab (Praluent®) and evolocumab (Repatha®)) for hypercholesterolaemia, neprilysin inhibition (sacubitril in combination with valsartan (Entresto®)) for heart failure, and interleukin-5 inhibition (mepolizumab (Nucala®)) for asthma., (© Royal College of Physicians 2016. All rights reserved.)

α-Eleostearic acid (α-ESA), or the cis-9, trans-11, trans-13 isomer of conjugated linolenic acid, is a special fatty acid present at high levels in bitter melon seed oil. The aim of this study was to examine the effect of α-ESA on hepatic lipid metabolism. Using H4IIEC3 hepatoma cell line, we showed that α-ESA significantly lowered intracellular triglyceride accumulation compared to α-linolenic acid (LN), used as a fatty acid control, in a dose- and time-dependent manner. The effects of α-ESA on enzyme activities and mRNA profiles in H4IIEC3 cells suggested that enhanced fatty acid oxidation and lowered lipogenesis were involved in α-ESA-mediated triglyceride lowering effects. In addition, α-ESA triggered AMP-activated protein kinase (AMPK) activation without altering sirtuin 1 (SIRT1) protein levels. When cells were treated with vehicle control (VC), LN alone (LN; 100μmol/L) or in combination with α-ESA (LN+α-ESA; 75+25μmol/L) for 24h, acetylation of forkhead box protein O1 was decreased, while the NAD(+)/NADH ratio, mRNA levels of NAMPT and PTGR1 and enzyme activity of nicotinamide phosphoribosyltransferase were increased by LN+α-ESA treatment compared to treatment with LN alone, suggesting that α-ESA activates SIRT1 by increasing NAD(+) synthesis and NAD(P)H consumption. The antisteatosis effect of α-ESA was confirmed in mice treated with a high-sucrose diet supplemented with 1% α-ESA for 5weeks. We conclude that α-ESA favorably affects hepatic lipid metabolism by increasing cellular NAD(+)/NADH ratio and activating PPARα, AMPK and SIRT1 signaling pathways., (Copyright © 2016 Elsevier Inc. All rights reserved.)

In continuation of our research program on Mediterranean dietary plants, a bioassay-guided fractionation of extracts from several accessions of Capparis sicula subsp. sicula and Capparis orientalis aerial parts was carried out. Antilipidemic activity of samples was assayed using inhibition of pancreatic lipase. To study the metabolic variability in Capparis species, HPTLC analyses were performed in order to characterize the species through the detection, isolation, and quantitative evaluation of rutin taken as significant chemical marker. The best activity was exerted by C. orientalis accession no. C10 and C. sicula subsp. sicula accession no. C6. The bioactivity evaluation of specific chemical markers, rutin and glucocapparin, led to the identification of a potent antilipidemic compound rutin. The HPTLC analysis showed large variation among the different analyzed samples with respect to rutin concentration. The chemical investigation showed a different composition between the species and between the collection zones. The variations showed by the studied accessions of caper could be attributed to exogenous factors. Capparis species contained predominantly quercetin rutinoside (rutin), accompanied by other constituents such as the glucosinolate glucocapparin. These rutin-rich extracts exhibited pronounced dose-dependent enzyme inhibitory activities toward pancreatic lipase., (© 2016 Verlag Helvetica Chimica Acta AG, Zürich.)

The search for indigenous natural antidiabetic and antilipidemec agents is still ongoing. Medicinal plants are widely used for this purpose. These herbs are very rich sources of bioactive compounds as flavonoids, polyphenols, tannins, alkaloids which have been reported as effective role to reduce blood glucose and lipid levels. Securigera securidaca seed is reputed in folk medicine for their value as antidiabetic and antilipidemec drugs. In this research, the effect of solvent polarity in bioactive extraction contents of this plant was evaluated by GC-MS analysis. Then antidiabetic and antilipidemic activies of different extracts were investigated in streptozotocine-induced diabetic rats and compared to glibenclamide as known chemical drug for diabetes.The results indicated that, carbon tetrachloride extract of Securigera securidaca seeds showed the best and significant hypoglycemic and hypolipidemic activities compared to other extracts because of its more sterols and fatty acids content with beta cells protecting effect from high glucose-induced apoptosis and also increasing in insulin level and sensitivity., (© Georg Thieme Verlag KG Stuttgart · New York.)

Phospholipids (PL) containing n-3 polyunsaturated fatty acids (PUFA) have beneficial effects of maintaining and promoting health compared with triacylglycerols (TAG) containing n-3 PUFA or general PL. This study evaluated the effects of dietary PL containing n-3 PUFA and elucidated the effects of the glycerophosphate structure and n-3 PUFA on fatty acid (FA) metabolism in rats. Rats were fed a basal diet containing soybean oil alone, TAG containing n-3 PUFA (1.8%), soybean PL (2.7%), PL containing n-3 PUFA (2.7%), or TAG containing n-3 PUFA (1.8%) + soybean PL (2.7%). The present n-3 PUFA-supplemented diets had similar FA compositions, and the PL diets had similar PL compositions. TAG containing n-3 PUFA reduced serum TAG contents, but did not affect serum cholesterol contents compared with soybean oil alone. PL diets containing n-3 PUFA and the combination of TAG containing n-3 PUFA and soybean PL resulted in decreased serum and liver TAG contents compared with the diet containing soybean oil alone, reflecting enhanced liver FA β-oxidation. The results of this study show that TAG containing n-3 PUFA with added soybean PL affects serum and liver TAG and cholesterol contents to a similar degree as PL containing n-3 PUFA. TAG containing n-3 PUFA and soybean PL are widely used as functional food ingredients and pharmaceutical constituents and are inexpensive compared with PL containing n-3 PUFA. Therefore, the combination of TAG containing n-3 PUFA and soybean PL has potential as a useful and inexpensive component of functional foods.

Gemfibrozil is a widely used hypolipidemic and triglyceride lowering drug. Excess of the drug is excreted and discharged into the environment primarily via wastewater treatment plant effluents. Bacillus sp. GeD10, a gemfibrozil-degrader, was previously isolated from activated sludge. It is the first identified bacterium capable of degrading gemfibrozil. Gemfibrozil degradation by Bacillus sp. GeD10 was here studied through genome sequencing, quantitative proteomics and metabolite analysis. From the bacterial proteome of Bacillus sp. GeD10 1974 proteins were quantified, of which 284 proteins were found to be overabundant by more than 2-fold (FDR corrected p-value ≤0.032, fold change (log2) ≥ 1) in response to gemfibrozil exposure. Metabolomic analysis identified two hydroxylated intermediates as well as a glucuronidated hydroxyl-metabolite of gemfibrozil. Overall, gemfibrozil exposure in Bacillus sp. GeD10 increased the abundance of several enzymes potentially involved in gemfibrozil degradation as well as resulted in the production of several gemfibrozil metabolites. The potential catabolic pathway/modification included ring-hydroxylation preparing the substrate for subsequent ring cleavage by a meta-cleaving enzyme. The identified genes may allow for monitoring of potential gemfibrozil-degrading organisms in situ and increase the understanding of microbial processing of trace level contaminants. This study represents the first omics study on a gemfibrozil-degrading bacterium.

Human cytochrome P450 (CYP) 2C enzymes metabolize ∼30% of clinically prescribed drugs and various environmental chemicals. CYP2C8, an important member of this subfamily, metabolizes the anticancer drug paclitaxel, certain antidiabetic drugs, and endogenous substrates, including arachidonic acid, to physiologically active epoxyeicosatrienoic acids. Previous studies from our laboratory showed that microRNA 107 (miR107) and microRNA 103 downregulate CYP2C8 post-transcriptionally. miR107 is located in intron 5 of the pantothenate kinase 1 (PANK1) gene. p53 has been reported to coregulate the induction of PANK1 and miR107. Here, we examine the possible downregulation of CYP2C8 by drugs capable of inducing miR107. Hypolipidemic drugs, such as bezafibrate, known activators of the peroxisome proliferator-activated receptor α (PPARα), induce both the PANK1 gene and miR107 (∼2.5-fold) in primary human hepatocytes. Surprisingly, CYP2C8 mRNA and protein levels were induced by bezafibrate. CYP2C8 promoter activity was increased by ectopic expression of PPARα in HepG2 cells, with a further increase after bezafibrate (∼18-fold), 4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio acetic acid (∼10-fold) treatment, or the antidiabetic drug rosiglitazone, all known PPAR activators. Promoter sequence analyses, deletion studies, mutagenesis studies, and electrophoretic mobility shift assays identified a PPARα response element located at position -2109 base pair relative to the translation start site of CYP2C8. Chromatin immunopreciptation assay analysis confirmed recruitment of PPARα to this PPARα response element after bezafibrate treatment of human hepatocytes. Thus, we show for the first time that CYP2C8 is transcriptionally regulated by PPARα, suggesting the potential for drug-drug interactions due to upregulation of CYP2C8 by PPAR activators., (U.S. Government work not protected by U.S. copyright.)

Gemfibrozil (GEM), which decreases serum triglycerides and low density lipoprotein, perpetrates drug-drug interactions (DDIs) with several drugs. These DDIs are primarily attributed to the inhibition of drug transporters and metabolic enzymes, particularly cytochrome P450 (CYP) 2C8 by the major circulating metabolite gemfibrozil 1-O-β-glucuronide (GG). Here, we characterized the transporter-mediated hepatic disposition of GEM and GG using sandwich-cultured human hepatocytes (SCHH) and transporter-transfect systems. Significant active uptake was noted in SCHH for the metabolite. GG, but not GEM, showed substrate affinity to organic anion transporting polypeptide (OATP) 1B1, 1B3, and 2B1. In SCHH, glucuronidation was characterized affinity constants (Km) of 7.9 and 61.4 μM, and biliary excretion of GG was observed. Furthermore, GG showed active basolateral efflux from preloaded SCHH and ATP-dependent uptake into membrane vesicles overexpressing multidrug resistance-associated protein (MRP) 2, MRP3, and MRP4. A mathematical model was developed to estimate hepatic uptake and efflux kinetics of GEM and GG based on SCHH studies. Collectively, the hepatic transporters play a key role in the disposition and thus determine the local concentrations of GEM and more so for GG, which is the predominant inhibitory species against CYP2C8 and OATP1B1.

Drugs affecting more than one target could result in a more efficient treatment of multifactorial diseases as well as fewer safety concerns, compared to a one-drug one-target approach. Within our continued efforts towards the design of multifunctional molecules against atherosclerosis, we hereby report the synthesis of 17 new morpholine derivatives which structurally vary in terms of the aromatic substitution on the morpholine ring. These derivatives simultaneously suppress cholesterol biosynthesis through SQS inhibition (IC50 values of the most active compounds are between 0.7 and 5.5 μM) while exhibiting a significant protection of hepatic microsomal membranes against lipid peroxidation (with IC50 values for the most active compounds being between 73 and 200 μM). Further evaluation of these compounds was accomplished in vivo in an animal model of acute experimental hyperlipidemia, where it was observed that compounds reduced the examined lipidemic parameters (TC, TG and LDL) by 15-80%. In order to examine the mode of binding of these molecules in the active catalytic site of SQS, we also performed docking simulation studies. Our results indicate that some of the new compounds can be considered interesting structures in the search for new multifunctional agents of potential application in atherosclerosis., (Copyright © 2015. Published by Elsevier Ltd.)

Novel formulations that overcome the solubility limitations of poorly water soluble drugs (PWSD) are becoming ever more critical to a drug development process inundated with these compounds. There is a clear need for developing bio-enabling formulation approaches to improve oral bioavailability for PWSD, but also to establish a range of predictive in vitro and in silico biopharmaceutics based tools for guiding formulation design and forecasting in vivo effects. The dual aim of this study was to examine the potential for a novel lipid based formulation, termed a lipidic dispersion, to enhance fasted state oral bioavailability of fenofibrate, while also assessing the predictive ability of biorelevant in vitro and in silico testing. Formulation as a lipidic dispersion improved both dissolution and solubilisation of fenofibrate through a combination of altered solid state characteristics and incorporation of solubilising lipidic excipients. These changes resulted in an increased rate of absorption and increased maximal plasma concentrations compared to a commercial, micronised product (Lipantil® Micro) in a pig model. Combination of biorelevant in vitro measurements with in silico physiologically based pharmacokinetic (PBPK) modelling resulted in an accurate prediction of formulation performance and forecasts a reduction in food effects on fenofibrate bioavailability through maximising its fasted state dissolution., (Copyright © 2015 Elsevier B.V. All rights reserved.)

The activation of sterol regulatory element binding proteins (SREBPs) is regulated by insulin-induced genes 1 and 2 (Insig-1 and Insig-2) and SCAP. We previously reported that feeding R-α-lipoic acid (LA) to Zucker diabetic fatty (ZDF) rats improves severe hypertriglyceridemia. In this study, we investigated the role of cyclic AMP-responsive element binding protein H (CREBH) in the lipid-lowering mechanism of LA and its involvement in the SREBP-1c and Insig pathway. Incubation of McA cells with LA (0.2 mM) or glucose (6 mM) stimulated activation of CREBH. LA treatment further induced mRNA expression of Insig-1 and Insig-2a, but not Insig-2b, in glucose-treated cells. In vivo, feeding LA to obesity-induced hyperlipidemic ZDF rats activated hepatic CREBH and stimulated transcription and translation of Insig-1 and Insig-2a. Activation of CREBH and Insigs induced by LA suppressed processing of SREBP-1c precursor into nuclear SREBP-1c, which subsequently inhibited expression of genes involved in fatty acid synthesis, including FASN, ACC and SCD-1, and reduced triglyceride (TG) contents in both glucose-treated cells and ZDF rat livers. Additionally, LA treatment also decreased abundances of very low density lipoprotein (VLDL)-associated apolipoproteins, apoB100 and apoE, in glucose-treated cells and livers of ZDF rats, leading to decreased secretion of VLDL and improvement of hypertriglyceridemia. This study unveils a novel molecular mechanism whereby LA lowers TG via activation of hepatic CREBH and increased expression of Insig-1 and Insig-2a to inhibit de novo lipogenesis and VLDL secretion. These findings provide novel insight into the therapeutic potential of LA as an anti-hypertriglyceridemia dietary molecule., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The cardioprotective influence of dietary fibre-rich fenugreek seeds and the well-established hypolipidemic spice garlic was evaluated both individually and in combination in isoproterenol induced myocardial infarcted rats. It was particularly examined whether pretreatment with dietary fenugreek, garlic or fenugreek + garlic would be beneficial under hypercholesterolemic conditions by their influence on the tissue lipid profile. Four groups each of male Wistar rats were maintained on either a basal diet or a high cholesterol diet for 8 weeks. Dietary interventions with fenugreek, garlic and the combination of fenugreek and garlic were made by including 10% fenugreek seed powder, 2% freeze-dried garlic powder, and 10% fenugreek seed powder + 2% garlic powder. At the end of the diet regimen, myocardial infarction was induced with isoproterenol (i.p. 80 mg kg(-1)) twice at intervals of 12 h. The disturbed activities of cardiac marker enzymes in serum and the heart confirmed isoproterenol induced myocardial infarction. Dietary fenugreek, garlic or fenugreek + garlic was found to ameliorate the pathological changes in heart tissue and lipid abnormalities in serum and the heart, the beneficial effect being higher with the combination of fenugreek and garlic, invariably amounting to an additive effect. The results also indicated that the hypercholesterolemic situation aggravated the myocardial damage during isoproterenol-induced myocardial infarction. This dietary intervention study suggested that the combination of fenugreek seeds and garlic offers a higher beneficial influence in exerting the cardioprotective effect.

While co-administered gemfibrozil can increase the area under the concentration/time curve (AUC) of pioglitazone more than 3-fold, the underlying mechanism of the drug-drug interaction between gemfibrozil and pioglitazone has not been fully understood. In the present study, gemfibrozil preincubation time-dependently inhibited the metabolism of pioglitazone in the cytochrome P450 (CYP)- and UDP-glucuronosyltransferase (UGT)-activated human liver microsomes. We estimated the kinact and K'app values, which are the maximum inactivation rate constant and the apparent dissociation constant, of gemfibrozil to be 0.071 min(-1) and 57.3 μM, respectively. In this study, the kobs, in vivo value was defined as a parameter that indicates the potency of the mechanism-based inhibitory effect at the blood drug concentration in vivo. The kobs, in vivo values of potent mechanism-based inhibitors, clarithromycin and erythromycin, were estimated to be 0.0096 min(-1) and 0.0051 min(-1), respectively. The kobs, in vivo value of gemfibrozil was 0.0060 min(-1), which was comparable to those of clarithromycin and erythromycin, suggesting that gemfibrozil could be a mechanism-based inhibitor as potent as clarithromycin and erythromycin in vivo., (Copyright © 2015 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.)

Traditional Chinese medicine (TCM) has definitely clinical effect in treating hyperlipidemia, but the action mechanism still need to be explored. Based on consulting Chinese Pharmacopoeia (2010), all the lipid-lowering Chinese patent medicines were analyzed by associated rules data mining method to explore high frequency herb pairs. The top three couplet medicines with high support degree were Puerariae Lobatae Radix-Crataegi Fructus, Salviae Miltiorrhizae Radix et Rhizoma-Crataegi Fructus, and Polygoni Multiflori Radix-Crataegi Fructus. The 20 main ingredients were selected from the herb pairs and docked with 3 key hyperlipidemia targets, namely 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase), peroxisome proliferator activated receptor-α (PPAR-α ) and niemann-pick C1 like 1 (NPC1L1) to further discuss the molecular mechanism of the high frequency herb pairs, by using the docking program, LibDock. To construct evaluation rules for the ingredients of herb pairs, the root-mean-square deviation (RMSD) value between computed and initial complexes was first calculated to validate the fitness of LibDock models. Then, the key residues were also confirmed by analyzing the interactions of those 3 proteins and corresponding marketed drugs. The docking results showed that hyperin, puerarin, salvianolic acid A and polydatin can interact with two targets, and the other five compounds may be potent for at least one of the three targets. In this study, the multi-target effect of high frequency herb pairs for lipid-lowering was discussed on the molecular level, which can help further researching new multi-target anti-hyperlipidemia drug.

Quantification of drug metabolites in biological samples has been of great interest in current pharmaceutical research, since metabolite concentrations and pharmacokinetics can contribute to a better understanding of the toxicity of drug candidates. Two major categories of Phase II metabolites, glucuronide conjugates and glutathione conjugates, may cause significant drug toxicity and therefore require close monitoring at early stages of drug development. In order to achieve high precision, accuracy, and robustness, stable isotope-labeled (SIL) internal standards (IS) are widely used in quantitative bioanalytical methods using liquid chromatography and tandem mass spectrometry (LC-MS/MS), due to their capability of compensating for matrix effects, extraction variations and instrument response fluctuations. However, chemical synthesis of SIL analogues of Phase II metabolites can often be very difficult and require extensive exploratory research, leading to higher cost and significant delays in drug research and development. To overcome these challenges, we have developed a generic method which can synthesize SIL analogues of Phase II metabolites from more available SIL parent drugs or SIL conjugation co-factors, using in vitro biotransformation. This methodology was successfully applied to the bio-generation of SIL glucuronide conjugates and glutathione conjugates. The method demonstrated satisfactory performance in both absolute quantitation and assessment of relative exposure coverage across species in safety tests of drug metabolites (MIST). This generic technique can be utilized as an alternative to chemical synthesis and potentially save time and cost for drug research and development.

Plant polyphenols, such as hydrolysable tannins, are present in the human diet and known to exhibit anti-diabetic and anti-obesity activity. We previously reported that the representative hydrolysable tannin compound α-penta-galloyl-glucose (α-PGG) is a small molecule insulin mimetic that, like insulin, binds to insulin receptor (IR) and activates the IR-Akt-GLUT4 signaling pathway to trigger glucose transport and reduce blood glucose levels in db/db and ob/ob diabetic mice. However, its effects on adipogenesis and lipid metabolism were not known. In this study, high fat diet (HFD)-induced diabetic and obese mice were treated with α-PGG to determine its effects on blood glucose and triglycerides. 3T3-L1 preadipocytes were used as a cell model for identifying the anti-adipogenic activity of α-PGG at molecular and cellular levels as a first step in elucidating the mechanism of action of the compound. In vivo, oral administration of α-PGG significantly reduced levels of blood glucose, triglyceride, and insulin in HFD-induced diabetic/obese mice (P<0.05). In vitro, α-PGG inhibited the differentiation of 3T3-L1 preadipocytes into mature adipocytes. α-PGG suppressed the expression of positive adipogenic factors PPARγ C/EBPα and mTOR and augmented the negative adipogenic factor Pref-1. Furthermore, α-PGG induced upregulation of p21 and G1 phase cell cycle arrest. In contrast, adipogenic signaling pathways mediated by insulin, the cAMP response element binding protein (CREB) and glucocorticoid receptor (GR), were not inhibited. RNAi knockdown of p21 led to a 4-fold increase in triglyceride level in 3T3-L1 preadipocytes treated with MDI and α-PGG compared to regular preadipocytes. These results indicate, for the first time, that α-PGG is blood triglyceride- and glucose-lowering in HFD-induced obese and diabetic mice. It selectively inhibited some but not all major adipogenic pathways as well as the mTOR-p21-mediated cell cycle regulatory pathway. It is very likely that these apparently diverse but coordinated activities together inhibited adipogenesis. These results expand our knowledge on how PGG works in adipocytes and further confirm that α-PGG functions as an orally-deliverable natural insulin mimetic with adipogenetic modulatory functions., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background: The antioxidant capacity and hypolipidaemic effects of Vigna unguiculata, as well as their potential improvement by different fermentation and thermal processes were studied using in vitro and in vivo methods., Results: Phenolic content and reducing capacity of legume acetone extract were significantly increased by different fermentation processes, and by the thermal treatment of fermented legume flours. TBARS inhibiting capacity was increased by fermentation but not by thermal treatment. A higher ability to decrease Cu(2+)/H2O2-induced electrophoretic mobility of LDL was found in fermented when compared to raw legume extracts, and a higher protective effect on short term metabolic status of HT-29 cells was found for raw and lactobacillus-fermented Vigna followed by naturally fermented Vigna extracts. Significant improvements in plasma antioxidant capacity and hepatic activity of antioxidant enzymes were observed in rats that consumed fermented legume flours when compared to the untreated legume or a casein-methionine control diet. In addition, liver weight and plasma levels of cholesterol and triglycerides were also positively affected by untreated or naturally fermented Vigna., Conclusion: V. unguiculata has demonstrated its potential as a functional food with interesting antioxidant and lipid lowering properties, which can be further augmented by fermentation processes associated or not to thermal processing., (© 2014 Society of Chemical Industry.)